Understanding the Mechanism of a Gut Microbial Genotoxin Involved in Colorectal Carcinogenesis

了解肠道微生物基因毒素参与结直肠癌发生的机制

基本信息

批准号：
10316686
负责人：
Emily Patricia Balskus
金额：
$ 38.43万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10316686
关键词：
Achievement Affect Alkylating Agents American Anabolism Animal Model Biological Biology Boronic Acids Cancer Biology Cancer Etiology Cells Cessation of life Chemicals Chromosomal Instability Colitis associated colorectal cancer Colorectal Cancer DNA DNA Adducts DNA Damage DNA Double Strand Break DNA Sequence Alteration Development Diagnosis Disease Enzymes Escherichia coli Eukaryotic Cell Exposure to Funding Future Gene Cluster Genome Goals Grant Human Human Cell Line Human Microbiome In Vitro Incidence Individual Infection Inflammatory Bowel Diseases Island Knowledge Location Malignant Neoplasms Mediating Metabolic Pathway Metabolism Methods Microbiology Molecular Mus Mutagens Pathway interactions Patients Physiological Play Prevalence Production Proteobacteria Public Health Research Role Specificity Structure Techniques Toxicology United States Woman Work animal tissue cancer initiation cancer prevention cancer therapy carcinogenesis colon cancer patients colon carcinogenesis colorectal cancer prevention commensal bacteria crosslink genotoxicity guided inquiry gut bacteria gut microbes gut microbiota host-associated microbial communities in vivo Model inhibitor/antagonist insight interdisciplinary approach men microbial microbial community microbiome research mouse model peptide synthase polyketide synthase prevent programs small molecule small molecule inhibitor structural biology tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY Colorectal cancer (CRC) is the third most prevalent form of cancer in the US and the second leading cause of cancer deaths. Studies over the last several decades have revealed that the gut microbiota influences CRC, and recent work has implicated gut bacterial genotoxins as key effectors in cancer development and progression. One of the bacterial genotoxins most strongly connected to cancer is colibactin, a metabolite produced by human gut commensal bacteria, including certain E. coli strains, that possess a biosynthetic gene cluster termed the pks island. The increased prevalence of pks+ E. coli in CRC patients and the ability of pks+ strains to potentiate tumorigenesis in mouse models of CRC suggest colibactin may play a causal role in cancer progression. However, achieving a mechanistic understanding of colibactin's genotoxicity and contribution to CRC has been impeded by an inability to isolate and structurally characterize the active genotoxic metabolite(s). During the previous funding period of this grant, we gained critical information about colibactin's structure and mode of action by studying the enzymes involved in its biosynthesis. Most notably, we established that colibactin is a DNA alkylating agent and proposed a potential structure for the active genotoxin. The overall objective of this renewal application is to elucidate additional molecular mechanisms underlying colibactin's activity and role in CRC carcinogenesis. Building off of the central hypothesis that the genotoxic activity of colibactin derives from the formation of DNA interstrand cross-links (ICLs), our three specific aims will: 1) characterize the specificity and structure of colibactin-DNA ICLs; 2) develop small molecules that inhibit colibactin biosynthesis in microbial communities; 3) elucidate the physiological location and timing of colibactin-mediated DNA damage in CRC development. These advances will be enabled by our multidisciplinary approach, which merges knowledge and techniques from chemical biology, structural biology, microbiology, toxicology, and cancer biology. Overall, this effort will fill critical gaps in fundamental knowledge needed to elucidate the role of colibactin-producing gut bacteria in CRC carcinogenesis and ultimately impact cancer prevention, diagnosis, and treatment. Additionally, by successfully demonstrating that studying and manipulating individual disease-associated microbial pathways can provide key mechanistic insights, this work will also support and validate future efforts to understand how other gut microbial activities influence CRC initiation and development.

项目概要结直肠癌 (CRC) 是美国第三大常见癌症，也是导致人类死亡的第二大原因癌症死亡。过去几十年的研究表明，肠道微生物群影响结直肠癌，并且最近的研究表明肠道细菌基因毒素是癌症发生和进展的关键效应物。与癌症关系最密切的细菌基因毒素之一是大肠杆菌素，它是人类产生的代谢产物肠道共生细菌，包括某些大肠杆菌菌株，它们拥有称为 pks岛。结直肠癌患者中 pks+ 大肠杆菌的患病率增加以及 pks+ 菌株的增强能力结直肠癌小鼠模型中的肿瘤发生表明大肠杆菌素可能在癌症进展中发挥因果作用。然而，对大肠杆菌素的遗传毒性和对结直肠癌的贡献的机制了解一直很困难。由于无法分离和结构表征活性基因毒性代谢物而受到阻碍。期间在本次资助的前一个资助期间，我们获得了有关 colibactin 的结构和模式的重要信息通过研究参与其生物合成的酶来发挥作用。最值得注意的是，我们确定大肠杆菌素是一种 DNA烷化剂并提出了活性基因毒素的潜在结构。本次活动的总体目标更新申请旨在阐明大肠杆菌素的活性和作用背后的其他分子机制结直肠癌的致癌作用。基于大肠杆菌素的基因毒性活性源自的中心假设 DNA 链间交联 (ICL) 的形成，我们的三个具体目标将：1) 表征特异性 colibactin-DNA ICL 的结构和结构； 2）开发抑制微生物大肠杆菌素生物合成的小分子社区； 3）阐明结肠直肠癌中大肠杆菌素介导的DNA损伤的生理位置和时间发展。这些进步将通过我们的多学科方法来实现，该方法融合了知识和化学生物学、结构生物学、微生物学、毒理学和癌症生物学的技术。总体而言，这努力将填补阐明产生大肠杆菌素的肠道的作用所需的基础知识的关键空白 CRC 致癌过程中的细菌，并最终影响癌症的预防、诊断和治疗。此外，通过成功地证明研究和操纵个体疾病相关的微生物途径可以提供关键的机制见解，这项工作还将支持和验证未来的努力，以了解如何其他肠道微生物活动影响结直肠癌的发生和发展。